Publications referred to by reference numbering in this specification correspond to the reference list at the end of the specification.
Insulin resistance is characterised by diminished insulin sensitivity of target tissues including liver, skeletal muscle and adipocytes (1). It is a key factor in the pathogenesis of type II diabetes mellitus and is also associated with other pathological states, such as obesity, dyslipidaemia, hyperinsulinaemia, hypertension and cardiovascular disease. These clustering metabolic defects have been termed syndrome X” or “the insulin resistance syndrome” (2).
The molecular basis of insulin resistance is extremely complex and multifactorial. Defects in several steps of insulin action, such as the activation of insulin receptors, post-receptor signal transduction and the glucose transport effector system, have been implicated in this disease (3, 4). Defective insulin receptor kinase activity, reduced IRS-1 tyrosine phosphorylation and decreased PI-3 kinase activity were observed in both human type II diabetic patients as well as animal models such as ob/ob mice (5, 6).
In addition to the intrinsic defects of the insulin receptor and postreceptor signalling components, other circulating factors, such as TNF-α, leptin, free fatty acids (FFA) and amylin may also contribute to the pathogenesis of insulin resistance (7-11). For instance, amylin, a hormone co-secreted with insulin from pancreatic islet β-cells, has been shown to antagonise insulin's metabolic actions both in vivo and in vitro (12-16). It can inhibit insulin-stimulated glucose uptake and glycogen synthesis. In vivo administration of amylin resulted in hyperglycemia and induced insulin resistance, similar to that observed in type II diabetes. Although some earlier studies suggested that amylin's biological effects on fuel metabolism were only of pharmacological interest, more recent in vivo studies with an amylin-selective antagonist have strongly supported its physiological relevance (17). Moreover, amylin deficient mice showed increased insulin responsiveness and more rapid blood glucose elimination following glucose loading, further confirming the role of amylin in the causation of insulin resistance (18). Indeed, elevated levels of circulating amylin (hyperamylinemia) and an increased ratio of amylin to insulin were observed in patients with type II diabetes as well as other diseases associated with insulin resistance, such as obesity and glucose intolerance (19).
Despite these advances, the detailed cellular mechanisms of insulin resistance are far from clear and there is a need for new therapeutic and diagnostic modalities for this condition.